Tumour necrosis factor-alpha (TNF-alpha) plays a key role in orchestrating the complex events involved in inflammation and immunity. Accordingly, TNF-alpha has been implicated in a wide range of autoimmune and infectious diseases, but also in conditions such as obesity and insulin resistance. The regulation of TNF-alpha expression in man is indicated to be partly genetically determined. We therefore screened a 1263 bp section of the proximal promoter of the TNF-alpha gene for common genetic variants affecting the transcriptional activity of the gene. Here we report the characterization of a common functional polymorphism in the promoter region of the TNF-alpha gene, a C-->A substitution at position -863. Electromobility shift assays provided evidence for a distinct difference in the binding of monocytic and hepatic nuclear factors to the -863C and -863A alleles. The rare -863A allele was associated with 31% lower transcriptional activity ( P < 0.001) in chloramphenicol acetyltransferase (CAT) reporter gene studies in human hepatoblastoma (HepG2) cells, indicating that the-863C/A polymorphism influences the basal rate of transcription of the TNF-alpha gene in vitro. Allele frequencies were 0.83/0.17 amongst 254 apparently healthy men of Swedish origin, aged 35-50 years. In 156 men, the -863C/A polymorphism was associated with the serum TNF-alpha concentration, carriers of the rare A allele having a significantly lower TNF-alpha level ( P < 0.05). It is concluded that the common-863C/A polymorphism in the promoter region of the TNF-alpha gene is functional in vitro in monocytic and hepatic cells and influences the serum TNF-alpha concentration in vivo in healthy middle-aged men.

PCSK9 is present in the circulation in 2 forms: a mature form composed of the PCSK9 prodomain attached to its catalytic domain and a form that is the result of furin cleavage at the Arg218-Gln219 peptide bond. 10,11 Commercially available and proprietary ELISA methods have been capable of measuring Background-The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment. Methods and Results-Incident CVD was recorded by matching to national registries. After 15 years of follow-up, a total of 491 incident events (fatal and nonfatal myocardial infarctions, unstable angina, deaths from coronary heart disease, fatal and nonfatal ischemic strokes) were recorded. Cox proportional hazards model was used to calculate hazard ratios with 95% confidence intervals. Baseline serum PCSK9 concentration predicted incident CVD; concentration in quartile 4 compared with quartile 1 was associated with a hazard ratio of 1.69 (95% confidence interval, 1.30-2.19) after adjustment for sex. Further adjustment for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), triglycerides, hypertension, diabetes mellitus, smoking, overweight, obesity, physical inactivity, and statin use resulted in a decrease in the hazard ratio to 1.48 (95% confidence interval, 1.12-1.95). Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz. Received July 15, 2015; accepted February 12, 2016. Conclusions-Serum Leander et al PCSK9 and Incident Cardiovascular Events 1231total PCSK9 concentrations. 12 Total PCSK9 concentration in the circulation is reportedly influenced by common and rare PCSK9 gene variants, sex, use of statins, and diurnal variation. [13][14][15] Several demographic and metabolic parameters appear to correlate with serum PCSK9, including plasma LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein B (apoB), insulin, glucose, fibrinogen, C-reactive protein, smoking, and body mass index. 13,14 Reported correlations have typically been weak and inconsistent, with the exception of LDL cholesterol, apoB, and triglycerides, for which correlations were weak but consistent. Considering that PCSK9 has convincingly been shown to regulate LDL cholesterol via the LDL receptor, we hypothesized that the serum PCSK9 concentration would be associated with future CVD events. There are to date few published studies examining whether the circulating PCSK9 concentrations can predict CVD risk. Therefore, we undertook the present investigation. Methods Study DesignParticipants in this cohort study were randomly selected f...

INSIG2 is involved in adipocyte metabolism and body weight regulation.